In this proposal, we will focus on CD4 tumor immunity with the goal of generating long-lived CD4+ "memory" T cells specific for tumor antigen(s) that should in turn synergize with CD8 T cells to create long-lasting tumor immunity. We will attempt to activate tumor-specific CD4+ T cells in vivo by targeting the OX- 40 receptor. The OX-40 receptor is a lymphocyte-specific member of a growing family of receptors for membrane-bound and soluble cytokines that has been termed the tumor necrosis factor receptor (TNF-R) superfamily. In addition to the TNF-receptors, this family also contains the CD30 antigen, CD40, FAS (CD95), DR3, and 4-1BB, all of which are expressed predominantly on cells of haematopoietic lineage. The OX-40 receptor is a membrane-associated glycoprotein found primarily on activated CD4+ T cells and is not expressed on normal resting peripheral blood lymphocytes. Recently, we and others have shown that the OX-40 receptor can provide a potent costimulatory signal to drive T cell proliferation, and that this stimulus appears to be more pronounced at the effector T cell stage rather than the naive T cell stage. We have also shown that T cells isolated from inflammatory lesions in experimental autoimmune encephalomyelitis (EAE), which expressed the OX-40 receptor, were highly enriched for the T cells responding to autoantigen. The OX-40 receptor has recently been found on CD4+ T cells at the site of inflammation in cancer patients (tumors and tumor draining lymph nodes). Therefore, we should be able to target and activate/costimulate antigen-specific T cells via the OX-40 receptor in vivo and create an enhanced tumor-specific response in hosts vaccinated with autologous tumor. In addition we will try to further enhance T cell specific tumor immunity by engaging the 4-1BB receptor which has shown to enhance CD8+ T cell function in a tumor setting. We will also attempt to block activation induced cell death in tumor-antigen specific T cells by blocking the DR3 "death domain" receptor expressed on activated T cells. Manipulating the combination of the 3 TNF-receptor family members in a tumor setting should help attain long-lived tumor immunity for both CD4+ and CD8+ T cells.